The present invention is directed to mass spectrometer probes for measuring gas tensions. Mechanisms of tissue oxygenation are complex and are not completely understood. The experimental study of the interaction of blood flow, diffusion and metabolism require measurements of gas tensions with a high decree of spatial resolution. Capillary diameters typically range from 6 to 8 microns, which limit spatial resolution.
Oxygen microelectrodes have been used in two ways to measure tissue partial pressure of oxygen (TPO.sub.2) with micron range resolution: as a single electrode within a micropipette, driven into tissue with a micromanipulator; or as a flat array of multiple microelectrodes for the simultaneous measurement of several oxygen tensions at the tissue surface.
Mass spectrometry provides a number of advantages over electrode techniques for the study of tissue gas exchange, including an inherent ability to measure a variety of gases and providing exceptional sensitivity. In addition to measurements of TPO.sub.2, mass spectrometers can measure partial pressures of CO.sub.2 as well as several tracer gases introduced for the study of transport mechanisms. Measurements of tissue gas exchange for a series of gases with a spectrum of physical properties are useful for determining the dependence of transport on tissue and blood solubility, diffusivity and metabolism.
Membrane inlet mass spectrometry (MIMS) has been used to measure gas tensions in aqueous solutions, in both blood and tissue. No currently available MIMS system, however, can provide spatial resolution adequate for studies of gas tensions on a micron scale. The selected introduction of gas components of a fluid into a mass spectrometer has been a long-standing problem.
The prior art has disclosed two types of technologies for measuring liquid phase gas tensions. First, membrane inlet systems have been designed for use in mass spectrometers in which a gas sample is introduced into the mass spectrometer by diffusion through a membrane. These systems typically use a large surface area for the membrane (one square centimeter), which requires a large blood sample to make measurements, and which limits spatial resolution.
MIMS provide the ability to quantify a wide variety of gaseous and volatile species simultaneously. This general property of mass spectrometry contrasts sharply with electrochemical analytic approaches, which are typically restricted to the measurement of only one or two reactive species. Specifically, polarographic microelectrodes have been used to quantify tissue oxygen tension as well as tissue hydrogen clearance. They cannot measure tensions of other gases of interest.
Mass spectrometer techniques excel for the measurement of multiple species, including inert gases that are used as tracers in studies of gas exchange. There are some restrictions on the nature of molecules that can be examined with membrane inlet systems. MIMS is most suitable for use with low molecular weight, nonpolar molecules.
With such systems, the limited spatial resolution makes it impossible to measure gas tension gradients, an important factor in some research applications. The larger surface area required for mechanical stability substantially limits the time response. In addition, many of the membrane inlet systems that have been reported use a much higher gas sampling rate which leads to diffusional limitations in the liquid phase thereby making the device impossible to calibrate in situ. Membrane-covered electrodes have been very useful for physiological measurements of the partial pressures of certain gases in the liquid phase. These electrodes are available commercially for O.sub.2, CO.sub.2 and H.sub.2. Electrodes can be made very small at the probe tip thereby permitting an excellent spatial resolution.
Unfortunately, electrode approaches have two intrinsic limitations. First, they require a large gas sample rate. Secondly, only certain reactive gas species can be measured. Mass spectrometers are intrinsically able to measure gas tensions with a smaller gas sample rate than are electrodes. At present, all previous electrodes for O.sub.2 and CO.sub.2 have required a large enough gas sample to induce stirring, thereby making in situ calibration difficult. Further, membrane-covered electrodes can only measure reactive species and not gases that are physiologically inert.
The prior art patent literature has disclosed several technologies using membrane and capillary-based technologies for facilitating gas tension measurement. U.S. Pat. No. 5,306,412, for example, teaches the use of mechanical vibration to enhance the electrostatic dispersion of sample solutions into the small, highly charged droplets that can produce ions of solute species for mass spectrometric analysis. The vibration is effective at ultrasonic frequencies for solutions with flow rates, conductivities and surface tensions too high for stable dispersion by electrostatic forces alone as in conventional electrospray ionization.
U.S. Pat. No. 4,439,679 discloses a device for the measurement of the tension of blood gases and resistance of the skin to the flow of such gases. The invention comprises a body having a gas permeable boundary comprising two gas permeable membranes for placement on the skin of the subject, two gas collection chambers in the body connected to a gas analysis system, a heating device to heat the skin area under the boundary and control means operable to control the heating device.
U.S. Pat. No. 4,791,292 discloses a capillary membrane interface for a mass spectrometer. The probe includes conduit passageways for permitting bi-directional fluid flow through diffusion in the capillary. See also U.S. Pat. No. 5,078,135.
Each of the above devices has a number of deficiencies. There has been a long-felt need for a single membrane probe for use in conjunction with mass spectrometers which exclude water and polar compounds which provide extremely low gas sample rates using a novel pore structure. Such a probe could be utilized to measure gas tensions of gases found in blood and saline such as O.sub.2, CO.sub.2, He and Xenon. Such a membrane could provide no stirring effect, a high spatial resolution and rapid response speed. The prior art systems provide either no stirring effect or a rapid response time but not a combination of the two.
Also, prior systems have used a high gas sample rate which induced diffusional resistance in the liquid layers surrounding the membrane. The measurement system signal then depended partly on the amount of stirring of the liquid, as well as protein deposits on the membrane, neither of which could be controlled during the measurement. The calibration performed in vitro therefore could not apply to the probe during the measurements, and there was no accurate way to calibrate the system in situ.